The broad long-term objective of this Project is to obtain a fundamental understanding of the basic biophysical and physiological mechanisms of task induced contrasts in human functional magnetic resonance imaging (fMRI). This understanding can be expected to lead to improved fMRI technology, to contribute to knowledge about local control of cerebral hemodynamics, and to provide a basis for the application of fMRI to the field of neuroscience. Progress towards this objective in the previous funding period is described in 4 papers, 2 PhD dissertations, and 101 abstracts. The hypothesis of this Project is that dynamic blood oxygen level-dependent (BOLD) fMRI contrast is a complex integral of vascular and metabolic component that vary over time and space, and that with sufficient a complex integral of vascular and metabolic components that vary over time and space, and that with sufficient a priori information, measurement of particular aspects of the BOLD signal can provide unique information about the physiological events resulting from task activation. This hypothesis is tested in four specific aims, each of which involves parallel studies in humans and in the rat whisker-barrel cortex, an fMRI model that was developed in the previous funding period: (1) to determine the effects of vascular architecture on the fMRI signal; (2) to correlate the spatial extent of the fMRI signal with neuronal activation; (3) to better characterize fMRI temporal patterns; and (4) to pursue in greater depth the study of underlying physiological fluctuations. The research will be based on several recent breakthroughs including: (1) greatly enhanced fMRI spatial resolution through the use of partial k- space gradient-recalled echo-planar imaging; (2) use of embedded contrast for precise comparison of task-activation response to two independent variables; (3) enhanced understanding of underlying physiological fluctuations in fMRI data sets; and (4) refinements of the 3 T scanner for state-of-the-art sensitivity and stability using local gradient coli technology. The protocols of the new specific aims follow from the work of the previous funding period, but at increased specificity and detail based on the substantial progress that was made. Functional MRI is a truly significant advance towards the goal of understanding brain function, with enormous potential impact on human health. It is essential that it have a firm foundation that is based on rigorous biophysical and physiological studies.